一种羌活醇衍生物的合成和其抗类风湿关节炎活性及作用机制研究

Synthesis of a notolitholderivative and study on its anti-rheumatoid arthritis activity and mechanism of action

目的 设计合成一种新的羌活醇(Notopterol, Not)衍生物(NotC),对其抗炎、抗风湿性关节炎(Rheumatoid arthritis, RA)的作用进行评价,探讨其作用机制。方法 以Not结构为基础,采用化学合成的方法合成出羌活醇二氧化硫供体衍生物(NotC)。通过测量脂多糖诱导的RAW264.7细胞炎症模型的NO含量,λ-角叉菜胶引起的急性足肿胀大鼠模型的足肿胀度和胶原诱导的大鼠关节炎模型(CIA)的足肿胀度和炎症因子等指标,系统地评价了NotC抗炎和抗RA的作用。通过网络药理学的GO和KEGG分析以及分子对接等方法对NotC的作用机制进行探讨。结果 通过化学合成的方法成功合成出了目标化合物(NotC),核磁结果表明其结构与目标结构一致,高效液相测得其纯度为95.4%。体内外药效实验结果显示,NotC明显抑制了LPS诱导的RAW264.7细胞中NO的表达,抑制了λ-角叉菜胶诱导的大鼠急性炎症,能缓解CIA大鼠的关节炎并抑制炎症细胞因子的表达。网络药理学分析和分子对接表明,NotC可通过调节MAPK信号通路,发挥比Not更好的抗RA作用。结论 在抗炎和治疗RA方面,NotC比Not更有效。

Objective A new Notopterol(Not)derivative(NotC)was designed and synthesized,and its anti-inflammatory and anti-rheumatoid arthritis(RA)effects were evaluated,and its mechanisms was discussed.Methods Based on the structure of Not,this study synthesized Not-derived sulfur dioxide donor derivative(NotC)using chemical synthesis methods.This study systematically evaluated the anti-inflammatory and anti-RA effects of NotC by measuring the levels of NO in LPS-induced RAW264.7 cell inflammation model,the degree of acute foot swelling inλ-carrageenan-induced rat model,and the degree of foot swelling and expression of inflammatory factors in collagen-induced arthritis(CIA)rat model.The mechanisms of NotC were investigated through network pharmacological analysis by GO,KEGG enrichment and molecular docking.Results NotC was successfully synthesized using chemical synthesis methods,and its structure was confirmed to be consistent with the target structure through nuclear magnetic resonance.High-performance liquid chromatography revealed that the purity of NotC was 95.4%.In vitro and in vivo efficacy experiments showed that NotC significantly inhibited the expression of NO in LPS-induced RAW264.7 cells.NotC suppressed acute inflammation inλ-carrageenan-induced rats,and alleviated arthri-tis in CIA rats while inhibiting the expression of inflammatory cytokines.Network pharmacological analy-sis and molecular docking suggested that NotC exerted a better anti-RA effect by modulating the MAPK signaling pathway compared to Not.Conclusion NotC is more effective than Not in anti-inflammatory and treatment of RA.